β-(4-isopropenylphenyl)estra-4,9-dienes, their production, and pharmaceutical preparations containing same

ABSTRACT

11 β-(4-isopropenylphenyl)-estra-4,9-dienes of general Formula I ##STR1## wherein X is an oxygen atom or a hydroxyimino grouping ##STR2## R 1  is a hydrogen atom or a methyl group, R 2  is a hydrogen atom or an acyl residue of 1-10 carbon atoms, 
     R 3  is a hydrogen atom, the cyanomethyl group, --(CH 2 ) n  --, CH 2  Z, --CH═CH--(CH 2 ) m  Z or --C═CC--Y wherein n=0 to 5 and m=1 to 4, Z meaning a hydrogen atom or the OR 4  group with R 4  meaning a hydrogen atom, an alkyl or alkanoyl group each of 1-4 carbon atoms, and Y meaning a hydrogen, chlorine, fluorine, iodine or bromine atom, an alkyl, hydroxyalkyl, alkoxyalkyl or acyloxyalkyl group each of 1-4 carbon atoms in the alkyl or acyl residue, possess antiprogestational activity, e.g., for treating hormonal dependent tumors, and also antiglucocorticoidal activity.

This application is a continuation of application Ser. No. 07/300,890,abandoned filed Jan. 24, 1989, which is a continuation-in-part ofApplication Ser. No. 07,077,359, filed July 24, 1987, now U.S. Pat. No.4,814,327.

BACKGROUND OF THE INVENTION

The invention relates to novel 11β-(4-isopropenylphenyl)-4,9-estradienes, processes for their production,and pharmaceutical preparations containing same.

11 α-(4-Isopropylphenyl)-4,9-estradienes and their antiglucocorticoidactivity are known from U.S. Pat. No. 4,540,686.

SUMMARY OF THE INVENTION

It is an object of this invention to provide new compounds havingvaluable pharmacological properties.

Upon further study of the specification and appended claims, furtherobjects and advantages of this invention will become apparent to thoseskilled in the art.

These objects have been attained by providing the compounds of thisinvention characterized by Formula I ##STR3## wherein X is an oxygenatom or a hydroxyimino grouping ##STR4## R¹ is a hydrogen atom or amethyl group, R² is a hydrogen atom or an acyl residue of 1-10 carbonatoms,

R³ is a hydrogen atom, the cyanomethyl group, --(CH₂)_(n) --CH₂ Z,--CH═CH--(CH₂)_(m) Z or --C═C--Y wherein n=0 to 5 and m=1 to 4, Zmeaning a hydrogen atom or the OR⁴ group with R⁴ meaning a hydrogenatom, an alkyl or alkanoyl group each of 1-4 carbon atoms, and Y meaninga hydrogen, chlorine, fluorine, iodine or bromine atom, an alkyl,hydroxyalkyl, alkoxyalkyl or acyloxyalkyl group each of 1-4 carbon atomsin the alkyl or acyl residues.

Suitable alkyl, alkanoyl and alkoxy groups for R⁴ and Y contain 1-4carbon atoms wherein the methyl, ethyl, propyl, acetyl propionyl,butyryl, methoxy and ethoxy groups are preferred also suitable beingbutyl, formyl, propoxy and butoxy and all isomers thereof. When R²stands for an acyl residue, then the formyl, acetyl, propionyl, butyryland benzoyl groups are preferred. The foregoing alkyl portions and acylportions are also suitable for use in the other groups for Formula I,e.g., acyloxyalkyl for Y, etc.

Among the general alkenyl residues, the propenyl and butenyl groups arepreferred, which can be present in the E or Z configuration, i.e., if R³stands for -CH═CH--(CH₂)_(m) Z, then m is to be preferably 1 or 2.

Preferred compounds of general Formula I are:

11 α-(4-isopropenylphenyl)-17 α-hydroxy-4,9-estradien-3-one

11 α-(4-isopropenylphenyl)-17α-hydroxy-17-(prop-1-ynyl)-4,9-estradien-3-one

11 α-(4-isopropenylphenyl)-17α-hydroxy-17-(prop-1(Z)-enyl)-4,9-estradien-3-one

11 α-(4-isopropenylphenyl)-17α-hydroxy-17-(3-hydroxyprop-1(Z)-enyl)-4,9-estradien-3-one

11 α-(4-isopropenylphenyl)-17α-hydroxy-17-(4-hydroxybut-1(Z)-enyl)-4,9-estradien-3-one

11 α-(4-isopropenylphenyl)-17 α-hydroxy-18-methyl-4,9-estradien-3-one

11 α-(4-isopropenylphenyl)-17α-hydroxy-18-methyl-17-(prop-1-ynyl)-4,9-estradien-3-one

11 α-(4-isopropenylphenyl)-17α-hydroxy-18-methyl-17-(prop-1(Z)-enyl)4,9-estradien-3-one

11 α-(4-isopropenylphenyl)-17α-hydroxy-18-methyl-17-(3-hydroxyprop-1(Z)-enyl)-4,9-estradien-3-one

11 α-(4-isopropenylphenyl)-17α-hydroxy-18-methyl-17-(4-hydroxybut-1(Z)-enyl)-4,9-estradien-3-one

11 α-(4-isopropenylphenyl)-17α-hydroxy-17-(3-hydroxy-propyl)-4,9-estradien-3-one

11 α-(4-isopropenylphenyl)-17α-hydroxy-18-methyl-17-(3-hydroxypropyl)-4,9-estradien-3-one

11 α-(4-isopropenylphenyl)-17α-hydroxy-17-methoxymethyl-4,9-estradien-3-one

11 α-(4-isopropenylphenyl)-17α-hydroxy-17-cyanomethyl-4,9-estradien-3-one.

The novel 11 α-(4-isopropenylphenyl)-4,9-estradienes of general FormulaI can be prepared according to this invention by a process characterizedin that, in a manner known per se, a compound of general Formula II##STR5## wherein R¹ has the meanings given above,

K is an acidically hydrolyzable keto blocking group, and

R^(2') and R^(3') have the same meanings as R2 and R³ wherein anypresent hydroxy groups are optionally blocked,

is subjected to the effect of an acidic agent capable of liberating theblocked function(s) and of selectively splitting off the 5 α-hydroxygroup with simultaneous formation of the 4(5)-double bond, andoptionally free hydroxy groups in the 17-position and/or in R^(3') areesterified or free hydroxy groups in R^(3') are etherified.

The starting compounds of general Formula II can be prepared from theepoxides of general Formula III ##STR6## (German Laid-Open ApplicationDE 33 47 126 A 1) wherein R¹ and K have meanings given above, Krepresenting, in particular, a form of the ketal, thioketal, oxime ormethyloxime, and R³ '^(') is a hydrogen atom or --C≡C--(CH₂)_(m) --OUwith m=1 to 4 and U meaning an acid-instable hydroxy blocking group.

Introduction of the 11 α-(4-isopropenylphenyl) residue with formation ofthe Δ⁹, ¹⁰ --5α-hydroxy structural element takes place conventionally inanalogy to the precesses set forth in European Patent ApplicationsPublication Nos. 57,115 and 110,434 by Cu(I)-catalyzed Grignard reactionwith the corresponding arylmagnesium halide (Tetrahedron Letters 1979 :2051) or by reaction of the corresponding homo- or heterocuprate of thetypes Ar₂ -CuLi and Ar₂ Cu(CN)Li, etc. (J. Amer. Chem. Soc. 103 : 7672[1981]).

All starting materials are conventional or conventionally preparablefrom known starting materials.

The compounds obtained--optionally after conventional conversion of theC-17 substituent R^(3'') into the C-17 substitution pattern of thelastly desired meaning of R² and R³ in the final product of generalFormula I--exhibiting general Formula II ##STR7## wherein R¹ and K havethe above-mentioned meanings, R^(2') and R3' have the same meanings asR2 and R³ wherein any present hydroxy groups are optionally blocked,

are subsequently treated, for the selective splitting off of water withformation of the 4(5)-double bond and for the simultaneous removal ofany present blocking groups, with an acid or an acidic ion exchanger.The acid treatment takes place conventionally by dissolving the compoundof Formula II in a water-miscible solvent, such as aqueous methanol,ethanol or acetone, and treating the solution with catalytic amounts ofa mineral or sulfonic acid, such as hydrochloric acid, sulfuric acid,phosphoric acid, perchloric acid or p-toluenesulfonic acid, or anorganic acid, such as acetic acid, until water has been split off andblocking groups have been removed. The reaction, proceeding attemperatures of 0° C. to 100° C., can also be performed with an acidicion exchanger. The course of the reaction can be observed withanalytical methods, e.g., by thin-layer chromatography of withdrawnsamples.

The blocking groups covered in general Formulae II and III by K andR^(3') and K and R^(3"), respectively, are groups readily cleavable inan acidic medium, for example the ethylenedioxyketal,ethylenedithioketal, 2,2-dimethyltrimethylenedioxyketal, hydroxyimino,methoxyimino , tetrahydropyranyl, methoxymethyl, or methoxyethyl group.

Substitution of the R^(3') hydrogen atom by the other residues includedfor R^(3') takes place according to the usual methods of construction ofC-17 side chains by nucleophilic addition to the 17-ketone, obtained byOppenauer oxidation of the C-17-hydroxy function, and by subsequentreactions ("Terpenoids and Steroids", Specialist Periodical Report, TheChemical Society, London, vol. 1-12).

Nucleophilic addition of HC≡CY wherein Y means hydrogen, alkyl of 1-4carbon atoms or halogen takes place with the aid of a compound of thegeneral formula MC≡CY wherein Y has the above meanings and M is analkali metal. The organometallic compound is produced by treatment ofthe corresponding acetylene with a base. In this process, the alkaliacetylide can be generated from the corresponding acetylene, forexample, by treatment with butyllithium or methyllithium in a suitablesolvent, preferably dialkyl ether, tetrahydrofuran, dioxane, benzene ortoluene.

For preparing the 17-chloroethynyl compound, the organometallicchloroethynyl compound is formed in situ from 1,2-dichloroethylene andan ethereal alkali metal solution, such as, for example, methyllithiumor butyllithium solution, and reacted with the 17-ketone in solvents,such as tetrahydrofuran or diethyl ether. 17-Haloethynyl compounds canalso be produced by halogenation of the corresponding ethynyl educt(Angew. Chemie 96 : 720 [1984]).

The introduction of 3-hydroxypropyne and, respectively, -propene in the17-position takes place by reaction of the 17-ketone with the dianion ofpropargyl alcohol, for example the dipotassium salt of propargyl alcoholgenerated in situ, to obtain the 17-(3-hydroxyprop-1-ynyl)-17 α-hydroxycompound, or with metallized derivatives of 3-hydroxypropyne, forexample with 1-lithium-3-(tetrahydropyran-2'-yloxy)prop-1-yn-1-ide, toobtain the 17-[3-(tetrahydropyran-2'-yolxy)propl-ynyl]-17 α-hydroxycompound which can subsequently be hydrogenated. This is accomplished,for example, by hydrogenation at room temperature and under normalpressure in solvents, such as methanol, ethanol, propanol,tetrahydrofuran, or ethyl acetate with the addition of modified noblemetal catalysts, such as platinum or palladium.

Introduction of the homologous hydroxyalkyne and hydroxyalkene groupstakes place correspondingly with homologs of propargyl alcohol.

The compounds with the Z-configured double bond in the hydroxyalkenylside chains are prepared by hydrogenation of the correspondingacetylenic structures with a deactivated noble metal catalyst (J. Fried,J.A. Edwards: Organic Reactions in Steroid Chemistry, Van NostrandReinhold Company, 1972, p. 134; H. O. House: Modern Synthetic Reactions1972, p. 19). Examples for suitable deactivated noble metal catalystsare 10% palladium on barium sulfate in the presence of an amine or 5%palladium on calcium carbonate with the addition of lead(II) acetate.Hydrogenation is terminated after absorption of one equivalent ofhydrogen.

The compounds with the E-configured double bond in the alkenyl sidechains are formed by reduction of the acetylenic structures in a mannerknown per se. Quite a number of methods are described in the literaturefor the conversion of alkynes into transolefins, for example thereduction with lithium aluminum hydride (J. Amer. Chem. Soc. 89 : 4245[1967]), with diisobutyl aluminum hydride and methyllithium (J. Amer.Chem. Soc. 89 : 5085 [1967]), or chromium(II) sulfate in the presence ofwater or dimethylformamide in a weakly acidic medium (J. Amer. Chem.Soc. 86 : 4358 [1964]), as well as generally reduction by the effect oftransition metal compounds with a change in the oxidation stage.

Introduction of 3-hydroxypropane in the 17-position takes place byreacting the 17-ketone with metallized derivatives of 3-halopropanols,wherein the hydroxy group is present in the metallizing step as thealcoholate (Tetrahedron Letters 1978 : 3013) or as a blocked function,to the 17-(3-hydroxypropyl)-17 α-hydroxy compound or to the compoundblocked on the terminal hydroxy group. The same blocking groups aresuitable as have been recited above for R^(3') and R^(3"), respectively.Introduction of the homologous hydroxyalkane groups takes placecorrespondingly with homologs of the 3-halopropanols.

The construction of the 17-cyanomethyl side chain takes placeconventionally from the 17-ketone, for example via the 17-spiroepoxideand cleavage of the spiroepoxide with HCN according to Z. Chem. 18 : 259(1978).

Free hydroxy groups in the 17-position and in the residues standing forR^(3') can be conventionally esterified or etherified.

The novel compounds of general Formula I are valuable pharmaceuticals.Thus, they exhibit strong affinity to the gestagen receptor withoutthemselves showing gestagen activity. They are competitive antagonistsof progesterone (antiprogestogens) and are suitable for triggeringabortion since they displace progesterone, necessary for maintainingpregnancy, from the receptor. They are, therefore, valuable and ofinterest with respect to their use for postcoital fertility control.They can also be used against gynaecological disorders, e.g.,endometriosis, dysmenorrhea, neoplastic diseases of the mammary glandand for inducing menstruation, and for initiating labor. Furthermore,they can be employed for the treatment of carcinomas depending onhormones. For example, various tumors of the genital tract and themammary glands, and meningiomas are known to possess receptors forovarian hormones such as estrogens and progesterone. The progression ofthe growth of these tumors can be fovorably influenced by antigestagentreatment per this invention.

The compounds of general Formula I according to this invention alsoexhibit antiglucocorticoid activity and thus can likewise be utilized asmedicines for the therapy of corticoid-induced disorders (e.g.,glaucoma) as well as for combating side effects occurring in thelong-term treatment with glucocorticoids (e.g..Cushing's syndrome).Therefore, they are capable of combating the disturbances caused bysupersecretion of the glucocorticoids, above all adipositas,arteriosclerosis, hypertension, osteoporosis, diabetes, as well asinsomnia.

When using the compounds of this invention for their antiglucocorticoidefficacy, in a preferred aspect, they will be used to treat conditionsfor which an antiprogestogenic effect is very well tolerated, e.g.,Cushing's disease, glaucoma, etc.

It has also been found that the novel compounds of general Formula Ishow, surprisingly, not only very good antiprogestational andantiglucocorticoid effects, but also exhibit a separation of the twoeffects.

For characterizing the antiprogestational activity, the abortiveefficacy was determined. The tests were performed on female ratsweighing about 200 g. After mating had taken place, the beginning ofpregnancy was ascertained by detection of sperm in vaginal smears. Theday of sperm detection is considered day 1 of gravidity (=dl p.c. (postcoitus)).

Treatment of the animals with the particular compound to be tested and,respectively, with the solvent took place after nidation of theblastocysts from d5 p.c. to d7 p.c. On d9 p.c., the animals weresacrificed and the uteri examined for implants and resorption sites.Photographs were prepared of all uteri. The absence of implants wasassessed as abortion.

The test compounds were dissolved in a benzyl benzoate-castor oilmixture (ratio 1+9). The vehicle volume per individual dose was 0.2 ml.Treatment was performed subcutaneously (s.c.).

The superiority of the compounds of this invention was demonstrated bycomparing the biological properties of the compound of this invention17-(3-hydroxypropl(Z)-enyl)-17 α-hydroxy-11α-(4-isopropenylphenyl)-4,9-estradien-3-one (A); 11α-(4-dimethylaminophenyl)-17 α-hydroxy-17-(propyn-1-yl)-4,9(10)-estradien-3-one RU 38486 (B), described in EP82400025.1 (U.S. Pat. Nos. 4,386,085, 4,447,424 and 4,519,946); 11α-(4-dimethylaminophenyl)-17 α-hydroxy-17-(3-hydroxypropyl)-4,9(10)-estradien-3-one (C), described in EP84101721.3 (U.S. Pat. No. 4,536,401); and 11α-(4-dimethylaminophenyl)-17 α-hydroxy-17-(3-hydroxyprop-1(Z)-enyl)-4,9(10)-estradien-3-one (D), described in EP84730147.0 (U.S. Pat. No. 4,609,651).

                  TABLE                                                           ______________________________________                                        Abortion Tests on Gravid Rats                                                                         Abortion rate                                                  Dose mg/Animal/Day                                                                           n - Abortion Positive/                                Compound s.c.           n - Total                                             ______________________________________                                        A        3.0            4/4                                                            1.0            4/4                                                            0.3            4/4                                                   B        3.0            4/4                                                            1.0            2/4                                                            0.3            0/4                                                   C        10.0           4/4                                                            3.0            4/4                                                            1.0            0/4                                                   D        3.0            4/4                                                            1.0            4/4                                                            0.3            0/4                                                   ______________________________________                                    

It can be seen from the table that, with a dose of 0.3 mg, only compound(A) according to this invention is fully effective abortively, i.e. thiscompound is more efficacious by a factor of 3-10 than the compounds ofthe state of the art.

To characterize the antiglucocorticoid effect, the effectiveness of thecompounds of this invention on tyrosine aminotransferase was determined.The test system is based on measuring the activity of liver enzymetyrosine aminotransferase (TAT) in cultures of RHC (rat hepatoma cells)cells. The enzyme catalyzes the first step of metabolizing of tyrosineand can be induced in the liver as well as in hepatoma cells byglucocorticoids. The activity can readily be measured in raw extracts(Granner and Tomkins [1970], Meth. Enzymol. 15 : 633). The enzymetransfers the amino group from tyrosine to 2-oxoglutaric acid. Duringthis process, glutamic acid and p-hydroxyphenylpyruvate are formed. Inalkaline solution, the more stable p-hydroxybenzaldehyde is formed fromp-hydroxyphenylpyruvate, with an absorption measured at 331 nm. The TATactivity in RHC cells shows a dose-dependent induction with cortisol(maximum activity at 10⁻⁶ M) or dexamethasone (maximum activity at 10⁻⁷M). The activity can be stimulated beyond the basic value by a factor of4-6. Simultaneous treatment with corticoid and antiglucocorticoid leadsto a decrease in TAT activity.

Compound (A) according to the invention shows, in this test, 2% of theactivity of RU 38486 (B), a compound to be considered as the standard(7th Int. Congress of Endocrinology July 1-7, 1984, Quebec City, Canada;Excerpta Medica, Amsterdam-Oxford-Princeton).

Since compound (A) shows a progestational activity which is ten timesstronger than that of (B), the result is thus a marked dissociation ofthe antiglucocorticoid and antiprogestational properties. A typicaldosage unit for any use of this invention contains about 1-100 mg ofactive compound(s). The dose of the compounds of this invention isapproximately 1-10,000 mg per day in the case of human patients. For theantiprogestational utilities, the general dosage range is 1-1000 mg,preferably 50-500 mg and the administration is analogous to the knownantiprogestational agent (RU 38486). For the antiglucocordicoidalactivity, the typical dosage range is 10-10,000, preferably 50-1000 mg,and the administration is analogous to the known antiglucocorticoidalagent (RU 38486). The preferred dosage range of the antigestageniccompounds of this invention for the mentioned hormone-dependentcarcinomas (tumors) is 10-200 mg/day/patient. Details of the use of agiven compound in this regard can be determined by routine testing usinga known protocol well correlated with human activity, e.g., those ofCancer Res. 1977, 37, S. 3344-3348; J. Med. Chem. 1985, 28:1880-1885;etc. Administration to treat carcinomas is analogous to such use for RU486.

The precise dosage for a given patient will be conventionally determinedaccording to the usual considerations including the condition of thepatient, the choice of the specific compound, etc., especially inconjunction with a conventional pharmacological protocol, e.g., onediscussed above.

Another outstanding property of the compounds of this invention is theirmetabolic stability which is high compared with prior-art compounds.Accordingly, the invention also relates to medicinal agents for treatingmammals including humans, based on the pharmaceutically acceptablecompounds of general Formula I, i.e. compounds that are nontoxic in thedoses utilized, and optionally the customary auxiliary agents andexcipients.

The compounds of this invention can be processed by conventional methodsof galenic pharmacy into pharmaceutical preparations for enteral,percutaneous, parenteral or local administration. They can beadministered in the form of tablets, dragees, gelatin capsules,granules, suppositories, implants, injectable sterile, aqueous or oilysolutions, suspensions or emulsions, ointments, creams, and gels. Theactive agent or agents can be mixed with the auxiliary materialscustomary in galenic pharmacy, such as, for example, gum arabic, talc,amylose, mannitol,smethylcellulose, lactose, tensides, such as "Tweens"or "Myrj", magnesium stearate, aqueous or non-aqueous vehicles, paraffinderivatives, surfactants, dispersion agents, emulsifiers, preservatives,and flavoring materials for improving taste (e.g. ethereal oils).Accordingly, the invention also- concerns pharmaceutical compositionscontaining as the active ingredient at least one compound according tothis invention.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description; utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainer of the disclosure in any way whatsoever.

In the foregoing and in the following examples, all temperatures are setforth uncorrected in degrees Celsius and unless otherwise indicated, allparts and percentages are by weight.

The entire text of all application, patents and publications, if any,cited above and below are hereby incorporated by reference.

EXAMPLE 117-(3-Hydroxyprop-1(Z)-enyl)-17β-hydroxy-11β-(4-isopropenylphenyl)-4,6-estradien-3-one

A solution of 2.21 g (3.49 millimoles) of17-[3-(tetrahydropyran-2-yloxy)prop-1(Z)-enyl]-11α-(4-isopropenylphenyl)-3,3-(2,2-dimethyltrimethylene-dioxy)-9-estrene-5α,178β-diolin 20 ml of 70% aqueous acetic acid is stirred for 60 minutes at 50° C.After cooling, the mixture is poured into ice water, neutralized byadding aqueous ammonia solution, and extracted with dichloromethane.Chromatography of the crude product on silica gel with a mixture ofethyl acetate/hexane yields 1.02 g of the desired compound.

[α]_(D) ²⁵ =+ 207°(c=0.50; CHCl₃)

The starting material is prepared as follows:

(a) At 40° C., a solution of 7.69 g (39 mmol) of1-bromo-4-isopropenylbenzene (Chem. Ber. 55 : 3406, 1922) in 40 ml ofabsolute THF is added to a suspension of 0.95 g (39 mmol)of magnesium in10 ml of absolute tetrahydrofuran (THF). After the magnesium has beencompletely dissolved, the mixture is cooled to +5° C., and 100 mg (1mmol) of copper chloride is added to the reaction solution. The solutionis stirred for 15 minutes and then, at 5° C., a solution of 2 g (3.9mmol) of17-[3-(tetrahydropyran-2-yloxy)prop-1-ynyl]-5α,10α-epoxy-3,3-(2,2-dimethyltrimethylenedioxy)-9(11)-estren-17β-olin 20 ml of absolute THF is added dropwise thereto. After this step, thereaction mixture is allowed to gradually warm up to room temperatureovernight, then it is poured into a mixture of ice water/aqueous ammoniasolution, and extracted with ethyl acetate. The resultant oily crudeproduct is chromatographed with ethyl acetate/hexane on aluminum oxide(Merck, stage III, neutral), thus obtaining 2.4 g of17-[3-(tetrahydropyran-2-yloxy)prop-1-ynyl]-11β(4-isopropenylphenyl)-3,3-(2,2-dimethyltrimethylenedioxy)-9-estrene-5α,17β-diol.

¹ H-NMR (CDCl₃): δ=0.47 ppm (s,3H,H-18); 2.15 (s,3H, CH₃ -olefin.); 4.8(s [broad], 1H,H-THP-ether); 5.05 and 5.4 (each s, each 1H,H-olefin.).

(b) A solution of 2.35 g (3.73 mmol) of the product obtained in (a) in37 ml of ethanol is hdyrogenated, after adding 2.4 ml of pyridine and235 mg of palladium/barium sulfate (10% Pd) at room temperature andunder normal pressure. After hydrogen absorption has ceased, the mixtureis filtered off from the catalyst and the filtrate is concentrated, thusobtaining 2.2 g of17-[3-(tetrahydropyran-2-yloxy)prop-1(Z)-enyl]-11β-(4-isopropenylphenyl)-3,3-(2,2-dimethyltrimethylenedioxy)-9-estrene-5α,17β-diol.

¹ H-NMR (CDCl₃): δ=0.49 ppm (s,3H,H-18); 2.15 (s,3H, -CH₃ -olefin.); 4.8(s [broad], 1H,H-THP-ether); 5.05 and 5.38 (each s, each 1H, H-olefin.);5.5-5.8 (m,2H,H-olefin. C-20 and C-21).

EXAMPLE 217-(4-Hydroxybut-1(Z)-enyl)-17β-hydroxy-11β-(4-isopropenylphenyl)-4,9-estradien-3-one

Analogously to the acidic cleavage described in Example 1, 2.5 g of17-(4-hydroxybut-1(Z)-enyl)-11β-(4-isopropenylphenyl)-3,3-(2,2-dimethyltrimethylenedioxy)-9-estrene-5α,17β-diolyields 1.28 g of the desired compound

[α]_(D) ²⁵ =+ 222° (CHCl₃ ; c=0.505)

The starting material is prepared as follows:

(a) Under a protective gas, 13.9 g of magnesium filings are combinedwith 175 ml of absolute tetrahydrofuran and mixed, in succession, with0.5 ml of dibromoethane and 96 g of 90% strength1-chloro-4-isopropenylbenzene, dissolved in 500 ml of absolutetetrahydrofuran. The reaction mixture is then heated to reflux until theGrignard reagent has been completely formed. Thereafter the solution iscooled to 0° C., and combined with 1.6 g of copper(I) chloride and thengradually with a solution of 42.5 g of5α-10α-epoxy-3,3-(2,2-dimethyltrimethylenedioxy)-9(11)-estren-17β-ol in250 ml of absolute tetrahydrofuran. The reaction mixture is graduallywarmed under agitation overnight to room temperature, then cooled to 0°C. and mixed with 250 ml of saturated ammonium chloride solution. Theorganic phase is separated from the aqueous phase and the latterextracted repeatedly with ethyl acetate. The combined organic phases arewashed with saturated sodium chloride solution, dried over sodiumsulfate, and concentrated under vacuum. The residue is chromatographedwith hexane/ethyl acetate on aluminum oxide (neutral, stage III), thusisolating 29.6 g of11β-(4-isopropenylphenyl)-3,3-(2,2-dimethyltrimethylenedioxy)-9-estrene-5α,17β-diolas a white foam.

¹ H-NMR (CD₂ Cl₂): δ=0.33 ppm (s,3H,H-18); 2.13 (s, 3H,CH₃ -olefin.);5.03 (s,1H,H-olefin.); 5.39 (s,1H,H-olefin.); 7.1-7.5 (m,4H, H-aromat.).

(b) Under a protective gas, 29 g of the compound obtained in (a) isdissolved in 600 ml of absolute toluene and combined, in succession,with 16 g of aluminum triisopropylate and 118 ml of cyclohexanone. Thereaction mixture is then heated to reflux, thus separating aboutone-third of the toluene via a water trap. After completing the reaction(thinlayer control), the reaction solution is cooled to room temperatureand mixed with saturated sodium bicarbonate solution. The thus-formedsuspension is filtered off over "Celite" and the filter residue rinsedthoroughly with ethyl acetate. The organic phase of the filtrate isseparated and the aqueous phase re-extracted several times with ethylacetate. The combined organic phases are dried over sodium sulfate andconcentrated under vacuum. The residue is chromatographed on aluminumoxide (neutral, stage III) with a mixture of ethyl acetate and hexane,thus isolating 23.4 g of11β-(4-isopropenylphenyl)-5α-hydroxy-3,3-(2,2-dimethyltrimethylenedioxy)-9-estren17-oneas a white foam.

¹ H-NMR (CDCl₃): δ=0.5 ppm (s,3H,H-18); 2.13 (s,3H, CH₃ -olefin.); 4.3(d J=6.5 Hz, 1H,H-11); 5.04 (s,1H,H-olefin.); 5.39 (s,1H,H-olefin.);7.17 (d J=8 Hz, 2H,H-aromat.); 7.37 (d J=8 Hz, 2H,H-aromat.).

IR (KBr): 1740 cm⁻¹ five-ring ketone

(c) 5 g of the steroid obtained in (b) is dissolved in 150 ml ofabsolute tetrahydrofuran and combined, in succession, with 17.15 g ofpotassium tert-butylate and 5.8 ml of 3-butyn-1-ol under a protectivegas at 0° C. The reaction mixture is then allowed to warm up graduallyto room temperature overnight, poured on saturated ammonium chloridesolution, and the aqueous phase is repeatedly extracted with ethylacetate. The combined organic phases are dried over sodium sulfate andconcentrated under vacuum. The residue is chromatographed on aluminumoxide (neutral, stage III) with a mixture of ethyl acetate/hexane, thusisolating 4.2 g of17-(4-hydroxybut-1-ynyl)-11β-(4-isopropenylphenyl)-3,3-(2,2-dimethyltrimethylenedioxy)-9-estrene-5α,17β-diolas a white foam.

IR (KBr): 2220 cm⁻¹ triple bond.

(d) Analogously to the directions given in Example 1 under (b), 4 g ofthe compound produced in (c) is reduced, thus isolating 3.95 g of17-(4-hydroxybut-1(Z)-enyl)-11β-(4-isopropenylphenyl)-3,3-(2,2-dimethyltrimethylenedioxy)-9-estrene-5α,17β-diolas a foamy crude product.

¹ H-NMR (CDCl₃ : δ=0.53 ppm (s,3H,H-18); 2.13 (s,3H, CH₃ -olefin.); 4.26(d J=6.5 Hz, H-11); 5.04 (s,1H,H-olefin.); 5.38 (s,1H,H-olefin.); 5.5(m,1H,H-olefin. C-21); 5.69 (d J=11 Hz, H-olefin. C-20); 7.1-7.45(m,4H,H-aromat.).

EXAMPLE 317-Methoxymethyl-17β-hydroxy-11β-(4-isopropenylphenyl)-4,9-estradien-3-one

In analogy to the acidic cleavage described in Example 1, 3 g of17-methoxymethyl-11β-(4-isopropenylphenyl)-3,3-(2,2-dimethyltrimethylenedioxy)-9-estrene-5α,17β-diolis converted into 1.48 g of the desired compound.

¹ H-NMR (CDCl₃): δ=0.56 ppm (s,3H,H-18); 2.13 (s,3H, CH₃ -olefin.); 3.22(d J=9.5 Hz, 1H,H-20); 3.43 (s,3H,CH_(3-O)); 3.57 (d J=9.5 Hz, 1H,H-20); 4.38 (d J=6.5 Hz, 1H,H-11); 5.06 (s,1H,H-olefin.); 5.38(s,1H,H-olefin.); 5.77 (s,1H,H-4); 7.14 (d J=8 Hz, 2H,H-aromat.); 7.39(d J=8 Hz, 2H,H-aromat.)

The starting material is produced as follows:

(a) Under a protective gas, 15 g of the intermediate product prepared inExample 2, directions under (b), is dissolved in 300 ml of absolutedimethylformamide and, at 0° C., combined in succession with 31.2 g oftrimethylsulfonium iodide and 18 g of potassium tert-butylate. Thereaction mixture is then warmed up gradually to room temperature underagitation overnight, thereafter poured on saturated ammonium chloridesolution, and the aqueous phase is repeatedly extracted with ethylacetate. The combined organic phases are dried over sodium sulfate,concentrated under vacuum, and the residue is chromatographed with amixture of ethyl acetate/hexane on aluminum oxide (neutral, stage III),thus isolating 13.4 g of11β-(4-isopropenylphenyl)-3,3-(2,2-dimethyltrimethylenedioxy)-9-estrene-[17(β1)spiro-3]oxiran-5α-olas a white foam.

¹ H-NMR (pyridine-d₅): δ=0.64 ppm (s,3H,H-18); 2.07 (s,3H,CH₃ -olefin.);2.57 (d J=5 Hz, 1H,H-20); 2.95 (d J=5 Hz, 1H,H-20); 4.36 (d J=6 Hz,1H,H-11); 5.01 (s,1H,H-olefin.); 5.07 (s,1H,H-olefin.); 7.32 (d J=8.5Hz, 2H,H-aromat.); 7.53 (d J=8.5 Hz, 2H,H-aromat.).

(b) Under a protective gas, 5 g of the compound prepared in (a) isdissolved in 100 ml of a 3-molar methanolic sodium methylate solutionand then heated to reflux for 3 hours. After cooling to roomtemperature, the reaction mixture is poured on water and the aqueousphase extracted repeatedly with ethyl acetate. The combined organicphases are dried over sodium sulfate and the solvents are evaporatedunder vacuum. The residue is chromatographed on aluminum oxide (neutral,stage III) with a mixture of ethyl acetate/hexane, thus isolating 4.5 gof17-methoxymethyl-11β-(4-isopropenylphenyl)-3,3-(2,2-dimethyltrimethylene-dioxy)-9-estrene-5α,17β-diolas a white foam.

¹ H-NMR (CDCl₃): δ=0.5 ppm (s,3H,H-18); 2.13 (s,3H,CH₃ -olefin.); 3.48(s,3H,CH₃ -O); 4.25 (d J=6 Hz, 1H,H-11); 5.04 (s,1H,H-olefin.); 5.38(s,1H,H-olefin.); 7.17 (d J=8.5 Hz, 2H,H-aromat.); 7.36 (d J=8.5 Hz,2H,H-aromat.).

EXAMPLE 417-Cyanomethyl-17α-hydroxy-11β-(4-isopropenylphenyl)-4,9-estradien-3-one

Analogously to the acidic cleavage described in Example 1, 3 g of17-cyanomethyl-11β-(4-isopropenylphenyl)-3,3-(2,2-dimethyltrimethylenedioxy)-9-estrene-5α,17β-diolyields 1.5 g of the desired compound.

¹ H-NMR (CDCl₃): δ=0.6 ppm (s,3H,H-18); 2.14 (s,3H, CH₃ -olefin.); 4.44(d J=6 Hz, 1H, H-11); 5.07 (s,1H,H-olefin.); 5.38 (s,1H,H-olefin.); 5.79(s,1H,H-4); 7.13 (d J=8 Hz, 2H,H-aromat.); 7.41 (d J=8 Hz, 2H,H-aromat.)

IR(KBr): 2260 cm⁻¹ nitrile.

The preparation of the starting material takes place in the followingway:

(a) Under a protective gas, 5 g of the compound prepared as per Example3, directions (a), is dissolved in 100 ml of ethanol and combined with asolution of 15 g of potassium cyanide in 33 ml of water. Subsequentlythe reaction mixture is heated overnight to 50° C., then poured on icewater, and the aqueous phase is extracted repeatedly with ethyl acetate.The combined organic phases are dried over sodium sulfate andconcentrated under vacuum. The residue is chromatographed on aluminumoxide (neutral, stage III) with a mixture of ethyl acetate and hexane,thus obtaining 4 g of17-cyanomethyl-11β-(4-isopropenylphenyl)-3,3-(2,2-dimethyltrimethylenedioxy)-9-estrene-5α,17β-diolas a white foam.

¹ H-NMR (CDCl₃): δ=0.52 ppm (s,3H,H-18); 2.13 (s,3H, CH₃ -olefin.); 4.32(d J=6.5 Hz, 1H,H-11); 5.04 (s,1H,H-olefin.); 5.39 (s,1H,H-olefin.);7.15 (d J=8 Hz, 2H,H-aromat.); 7.39 (d J=8 Hz, 2H,H-aromat.)

IR (KBr): 2250 cm⁻¹ nitrile.

EXAMPLE 517-(Prop-1-ynyl)-17β-hydroxy-11β-(4-isopropenylphenyl)-4,9-estradien-3-one

Analogously to the acidic cleavage disclosed in Example 1, 2.5 g of17-(prop-1-ynyl)-11β-(4-isopropenylphenyl)-3,3-(2,2-dimethyltrimethylenedioxy)-9-estrene-5α,17β-diol yields 1.36 g of the desired compound.

¹ H-NMR (CDCl₃): δ=0.52 ppm (s,3H.H-18); 1.77 (s,3H,H-22); 2.13(s,3H,CH₃ -olefin.); 4.43 (d J=6.5 Hz, 1H,H-11); 5.05 (s,1H,H-olefin.);5.37 (s,1H,H-olefin.); 5.78 (s.1H,H-4); 7.13 (d J=8 Hz, 2H,H-aromat.);7.4 (d J=8 Hz, 2H,H-aromat.).

The starting material is prepared as follows:

(a) 150 ml of absolute tetrahydrofuran is saturated with methylacetyleneby introducing the latter for 30 minutes at 0° C. Then, at a temperatureof between 0° and 5° C., 19 ml of a 15% strength solution ofn-butyllithium in hexane is added dropwise thereto; after this step, themixture is stirred for 15 minutes and then a solution of 3 g of theketone obtained in Example 2(b) in 25 ml of absolute tetrahydrofuran isgradually added. The reaction mixture is stirred for 2 hours, poured onwater, and the aqueous phase is extracted repeatedly with ethyl acetate.The combined organic phases are dried over sodium sulfate andconcentrated under vacuum. The residue is chromatographed with a mixtureof ethyl acetate/hexane on aluminum oxide (neutral, stage III), thusobtaining 2.73 g of17-(prop-1-ynyl)-11β-(4-isopropenylphenyl)-3,3-(2,2-dimethyltrimethylenedioxy)-9-estrene-5α,17β-diolas a white foam.

IR (KBr): 2230 cm⁻¹ triple bond.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. A method of treating a hormone-dependentcarcinoma comprising administering to a host in need of such treatmentan effective amount of a compound of the formula ##STR8## wherein X is Oor ##STR9## R¹ is hydrogen or methyl,R² is hydrogen, C₁₋₁₀ -alkanoyl orbenzoyl, R³ is hydrogen, cyanomethyl, --(CH₂)_(n) --CH₂ Z,--CH═CH--(CH₂)_(m) Z or --C C≡Y, n=0 to 5, m=1 to 4, Z is hydrogen orOR⁴, R⁴ is hydrogen, C₁₋₄ -alkyl or C₁₋₄ -alkanoyl, and Y is hydrogen,chlorine, fluorine, iodine, bromine, C₁₋₄ -alkyl, hydroxy-C₁₋₄ -alkyl,C₁₋₄ -alkoxy-C₁₋₄ -alkyl or acyloxy-C₁₋₄ -alkyl wherein acyl is C₁₋₄-alkanoyl or benzoyl.
 2. A method of claim 1 wherein X is
 0. 3. A methodof claim 1 wherein X is ##STR10##
 4. A method of claim 1 wherein R¹ isH.
 5. A method of claim 1 wherein R¹ is CH₃.
 6. A method of claim 1wherein R² is H.
 7. A method of claim 1 wherein R² is C₁₋₄ -alkanoyl. 8.A method of claim 1 wherein R³ is H.
 9. A method of claim 1 wherein R³is --CH₂ CN.
 10. A method of claim 1 wherein R³ is --(CH₂)_(n) CH₂ Z.11. A method of claim 1 wherein R³ is --CH═CH--(CH₂)_(m) Z.
 12. A methodof claim 1 wherein R³ is --C≡C--Y
 13. A method of claim 1, wherein saidcompound is: 11 β-(4-Isopropenylphenyl)-17β-hydroxy-4,9-estradien-3-one,1β-(4-isopropenylphenyl)-17β-hydroxy-17-(prop-1-ynyl)-4,9-estradien-3-one,11β-(4-isopropenylphenyl)-17β-hydroxy-17-(prop-1(Z)-enyl)-4,9-estradien-3-one,11β-(4-isopropenylphenyl)-17β-hydroxy-17-methoxymethyl-4,9-estradien-3-one,11β-(4-isopropenylphenyl)-17β-hydroxy-17-cyanomethyl-4,9-estradien-3-one,11β-(4-isopropenylphenyl)-17β-hydroxy-17-(3-hydroxyprop-1(Z)-enyl)-4,9-estradien-3-one,11β-(4-isopropenylphenyl)-17β-hydroxy-17-(4-hydroxybut-1(Z)-enyl)-4,9-estradien-3-one,11β-(4-isopropenylphenyl)-17β-hydroxy-18-methyl-4,9-estradien-3-one,11β-(4-isopropenylphenyl)-17β-hydroxy-18-methyl-17-(prop-1-ynyl)-4,9-estradien-3-one,11β-(4-isopropenylphenyl)-17β-hydroxy-18-methyl-17-(prop-1(Z)-enyl)-4,9-estradien-3-one,11β-(4-isopropenylphenyl)-17β-hydroxy-18-methyl-17-(3-hydroxyprop-1(Z)-enyl)-4,9-estradien-3-one,11β-(4-isopropenylphenyl)-17β-hydroxy-18-methyl-17-(4-hydroxybut-1(Z)-enyl)-4,9-estradien-3-one,11β-(4-isopropenylphenyl)-17β-hydroxy-17-(3-hydroxypropyl)-4,9-estradien-3-one,or11β-(4-isopropenylphenyl)-17β-hydroxy-18-methyl-17-(3-hydroxypropyl)-4,9-estradien-3-one,each a compound of claim
 1. 14. A method of claim 1, wherein said amountis 10-200 mg/day.
 15. A method of claim 1, wherein said compound isadministered in the form of a mixture with a pharmaceutically acceptablecarrier.
 16. A method of achieving an antiglucocorticoid effect in ahost comprising administering to said host a compound of the formula##STR11## wherein X is O or ##STR12## R¹ is hydrogen or methyl, Rhu 2 ishydrogen, C₁₋₁₀ -alkanoyl or benzoyl,R³ is hydrogen, cyanomethyl,--(CH₂)_(n) -CH₂ Z, --CH═CH--(CH₂)_(m) Z or --C═C--Y, n=0 to 5, m=1 to4, Z is hydrogen or OR⁴, R⁴ is hydrogen, C₁₋₄ -alkyl or C₁₋₄ -alkanoyl,and Y is hydrogen, chlorine, fluorine, iodine, bromine, C₁₋₄ -alkyl,hydroxy-C₁₋₄ -alkyl, C₁₋₄ -alkoxy-C₁₋₄ -alkyl or acyloxy-C₁₋₄ -alkylwherein acyl is C₁₋₄ -alkanoyl or benzoyl.
 17. A method of claim 16,wherein said effect is treatment of glaucoma, Cushing's syndrome,adipositas, arteriosclerosis, hypertension, osteoporosis, diabetes orinsomnia.